Background: Point of care testing for C-reactive protein (CRP) has shown promise as a measure to reduce unnecessary antibiotic prescribing in respiratory tract infections (RTI), but its use in primary care is still controversial. We aimed to evaluate the effect of CRP testing on the prescription of antibiotics, referral for radiography, and the outcome of patients in general practice with acute cough/RTI. Methods: An open-cluster randomized clinical trial was conducted, with CRP testing performed in the intervention group. Antibiotic prescribing and referral for radiography were the main outcome measures. Results: A total of 179 patients were included: 101 in the intervention group and 78 in the control group. The two groups were similar in clinical characteristics. In the intervention group, the antibiotic prescribing rate was 37.6%, which was significantly lower than that in the control group (58.9%) (P = 0.006). Referral for chest X-ray was also significantly lower in the intervention group (55.4%) than in the control group (75.6%) (P = 0.004). The recovery rate, as recorded by the GPs, was 92.9% and 93.6% in the intervention and control groups, respectively. Conclusion: The study showed that CRP testing in patients with acute cough/RTI may reduce antibiotic prescribing and referral for radiography, probably without compromising recovery. Trial registration: The trial was registered in the ClinicalTrials.gov Protocol Registration System (identification number: NCT01794819).